Does combination prokinetic therapy benefit patients with refractory diabetic gastroparesis?

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AGA ABSTRACTS

TESTING THE EFFICACY OF GAVISCON WITH A MECHANICAL MODEL OF GASTROESOPHAGEAL REFLUX (GER) JG Laufer, SS Kadirkamanathan, DF Evans. Gastrointestinal Science Research Unit, The London Hospital Medical College, London, UK Gaviscon is an antacid-alginnte formulation which prevents GER of gastric contents by development of a foam raft. Little data is available on the precise mechanisms by which CJavisconoperates and the raft reflux barrier may alter depending on pressure differences across the lower esophageal sphincter (LES) or LES position as in hiatus hernia. METHOD: We investigated the ability of Gaviscon (SKB USA) to prevent reflux in static and dynamic experiments using a previously developed mechanical model. A perspex chamber formed the gastric compartment on to which an artificial sphincter and thorax were attached. This was connected to a reservoir f'dled with NI0 hydrochloric acid. A balloon inside the gastric compartment enabled us to alter intra-abdominal pressure (IAP). Pressure changes in each compartmentwere measured and displayed on a chart recorder. GER was detected by measuring the flow rate of acid and Gaviscon through the LES and also by pH measured with a glass electrode placed 5 cm proximal to the LES. All experiments were performed with and without Gaviscon. Reflux was measured in static and dynamic situations (simulation of exercise with respirators) varyingLES length and pressure (LESP), IAP and intrathoracic pressure. RESULTS: Static experiments showed a reduction in flow rate when a Gaviscon raft was present. G-avisCondemonstratedthe most significantbarrier to reflux when the LEsP was equal to or less~than IGP. pH recordings showed that Gaviscon produced a shift in the threshold to reflux from 20mmHg LESP (no Gaviscon) to 15mmHg LESP (Gaviscon). However, it did not provide the same protection against GER in the presence of a short LES. During fluctuations of LESP and ether pressures with exercise simulations, reflux was lower with Gaviscon than without Qt~0.04). In experiments with different sphincter positions, Gaviscon was totally effective in preventing reflux when the LES was wholly in the abdomen but had some effect even when the LES was entirely thoracic. CONCLUSION:These experiments have demonstratedthat Gaviscon reduces the rate of GER in a mechanical model in static and dynamic situations and that the alginate raft maintained a barrier to reflux at lower LF~Ps when compared with no Gaviscon. Gaviscon was also effective in reflux prevention even when the LES was entirely intrathoracic as in hiatus hernia. This project was sponsored by SmithKline Beecham Consumer Healthcare Pittsburgh PP~ USA.

ELECTROGASTROGRAPHIC FINDINGS IN PATIENTS WITH FUNCTIONAL DYSPEPSIA ACCORDING TO GASTRIC 1~4PTYIN6TIME, kND AFTER ERYTHROMYCINTREATMENT. S. 1. L e e , Y.S. Park, d.H. Kim, K . B . Hahm, Y . S . Kim Department of Gastroenterology, Ajou University School of Medicicine, Suwon, Korea. The aim of this study was to deter=ine the relation between gastric myoelectrical activity and gastric emptying in 30 patients with functional dyspepsia (7 males and 23 females) and to investigate the effect of erythromycin on gastric slow wave. Methods: Gastric emptying study w a s performed on subjects given scrambled ~ with 2mCi 99m Tc-sulfur colloid and gastric myoelectrical activity was recorded by cutaneous electrogastrogral0hy (Synetics, Digitrappar EGG). EGn was recorded for at least 30-rain during fasting and then 30-rain after solid test meal (674 Call. Oral erythrmmycin 25Deg bid was aclainistered to the 15 patients for 2 weeks. Based on the ~ i n g power spectra, EGG was analyzed. Results: 1) 14 patients (46s) showed delayed gastric emptying time (GEl'). 2) In postprandial state, the ratio of normal slow wave (2-4cpm) in patients with normal GET was significantly higher compared to patients with delaymd GET (p(O. O5)(tuble). 3) Normal postprandial amplitude increment (1.5 times higher than prmprandial amplitude) was seen in 7 patients (50s) with delayed GET and in 13(80~) patients in normal GET, which was statistically si@aificant (p(O.05}. 5) in 7 patients out of 15 with substantial improvement of dyspeptic symptoms daring erythromycin therapy, normal slow wave was significantly increased compared to baseline EVA;, 97.9+-4.9~ vs 77.1--0.8~ in preprandial state (p(O.O05) and 98.6-I3.7~ vs 87.1±9.7~ in pestpraedial state (~0.01). 6) in 8 patients with little improvement, normal slow wave was not significantly changed in prmpreedial state, 92.9--7.1s vs 91,2+8.6s, but significantly reduced in postprandial state compared to baseline EC~, 73.6+-17.9s vs M.4---IO.3s (p(O.05). 7) ~tbnoreal postprandial amglitude chenge of slow wave in 6 pati--nats was 10rproved in 5 patients with simultaneous improvement of dyspeptic symptoms during erythroaycin treatment (p~0. 005).

Normal GET (n=16) Delayed GET (n=14)

Normal slow wave (2-4cpa) Postprandial amplitude preprandial (g) postprandial(s) increment, n(~) 88.4 +- 12.7 95.9 -+- 6.2* 13 (80)* 87.5+- 12.1 82.5+- 14.3, 7 (50)*

*p
GASTROENTEROLOGY,Vol. 108, No. 4

BILE ACID MODULATION OF ELECTROPHYSIOLOGY OF C I R C U L A R MUSCLE F R O M CANINE COLON. H.K. Lee, M. Homer, S.D. Koh, and K.M. Sanders. Deparment of Physlolosy, University of Nevada, Reno, NV 89557, U.S.A~

Under normal conditions with efficient entemhepatic circulation, less than 5 % of bile acids enters the colon. In some pathological conditions, such as ileal mucosa inflammation or following ileocecal resection, the reabsorption of bile acids is compromised, and these compounds pass into the colon. In the present study, we examined whether bile acids affect the electrical activities of circular smooth muscle of canine colon. Using intmc~ular recording techniques, we found that dilutions of canine bile (1, 2, 5 % by volume) depolarized the colonic muscle cells in a concentrationdependent manner by g, 15, 29 mV respectively. These effects were reversible. Individual components of the bile also affected electrical activity. Cholic acid (I0 "4 M) depolarized the membrane by 4 mV and increased slow wave amplitudes by 7 inV. Deoxycholic acid (10"4M) also depolarized the membrane by 4 mV and shortened the duration of slow waves. Tanrocholic acid (10~ M) increased the slow wave duration with little affect on membrane depolarization. To determine the ionic mechanisms responsible for the affects of bile acids, patch clamp studies were performed on fleshly dispersed smooth muscle cells from the circular muscle layer of the colon. The effects of bile acids were examined under cell voltage clamp at 33:1: I*C. Potassium currents were blocked by internal dialysis with Cs+, and the c r gradient was adjusted such that Ea" was equal to -70 mV. Canine bile (l, 2, 5 %) induced an inward current at a holdin 8 potential of-70 inV. Previously, we have shown that a similar current, identified as a non-selective cation current, can be activated by muscarinic stimulation (Lee et al., Am. J. Physiol. 265:C1463-1471, 1993). Deoxycholic acid 0 0 4 IV0 also activated a non-selective cation current. The non-selective cation current might explain the depolarizations caused by bile and components of bile in intact muscles. We tested this hypothesis using current clamp conditions. Bile ( 1 % ) depolarized the membrane potentials of isolated cells. This excitatory action of bile acids on colonic smooth muscle may explain some of the pathophysiological conditions accompanying defects in bile reabsorption. (Supported by DK 41315)

DOES COMBINATION PROKINETIC THERAPY BENEFIT PATIENTS WITH REFRACTORY DIABETIC GASTROPARESIS? KA Lehmann, DJ Patterson. Department of Medicine, Virginia Mason Medical Center, Seattle, WA. Diabetic Gastroparesis (DG) is a syndrome characterized by symptoms of nausea, vomiting, early satiety and in some pts abdominal pain, in the setting of delayed gastric emptying. Cisapride(C) stimulates motility through acetylcholine release and Domperidone (D), a dopamine antagonist, has additional central anti-emetic effects. We prospectively studied 9 pts previously treated with either C 20 mg QID or D 20 mg QID whose symptoms had become refr~Yctory to either drug alone. These pts were treated with both drugs at doses of 20 mg QID for a mean of 9 months (range 2-16 mos). Parameters assessed were: individual symptoms of nausea, vomiting, early satiety, bloating and abdominal pain on a 10point severity scale; frequency and duration of hospitalization for gastroparetic symptoms in the year prior to combination therapy and during combination therapy. All pts had type I diabetes, age range 27-40 yrs;duration of diabetes 4-27 yrs (mean 16 yrs). These pts had a higher incidence of abdominal pain (8/9) than previous studies have shown (usually _<1/3). Extensive investigations revealed no other causes for abdominal pain. Duration of DG averaged 42 mos (range 2-101 mos). Gastric emptying for solids by scintiscan was abnormal in 7/8, normal in I/8. 1 pt had absent peristalsis with food retention on UGI series and endoscopy. Results: Symptom scores for nausea, vomiting, satiety and bloating significantly improved with combination therapy. Abdominal pain was not improved. Frequency and average duration of hospitalization was unchanged compared to the previous yr (3.2 vs 3.8 hospitalizations per pt ;13.4 vs 15.3 days per hospitalization). Conclusions: Pts with symptoms of DG refractory to single-agent prokinetic therapy may benefit from combination therapy for most symptoms except abdominal pain. Hospitalizations are not reduced in this group of pts who also have intractable abdominal pain due to diabetic visceral neuropathy. Combination prokinetic therapy may be more effective if administered earlier in the course of DG.